Ciprofol alleviates remifentanil-induced hyperalgesia by regulating α2GABAARs, NR2B, and P-CaMKIIα levels in the spinal cord and hippocampus.

OBJECTIVES: Several studies have shown that propofol administration during surgery effectively attenuates remifentanil-induced hyperalgesia (RIH). Ciprofol, a novel intravenous sedative agent analogous to propofol, has not yet been proven efficacious in alleviating RIH. The present study aimed to investigate the effect of ciprofol on RIH and the possible mechanisms involved. METHODS: The RIH model was established by an infusion of remifentanil (1 µg·kg-1·min-1) 60 min in rats with incisional pain. Ciprofol (0.1, 0.25, and 0.4 mg·kg-1·min-1) was simultaneously infused to evaluate its effect on RIH. The antinociception of ciprofol was verified by measured paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). γ-aminobutyric acid type A receptor α2 subunit (α2GABAAR), N-methyl-d-aspartate receptor NR2B subunit (NR2B), calcium/calmodulin-dependent protein kinase II α (CaMKIIα), and phosphorylated CaMKIIα (P-CaMKIIα) in the spinal cord and hippocampus of rats were assessed by western blotting and immunohistochemistry. KEY FINDINGS: The results showed that ciprofol dose-dependently increased PWMT and PWTL values in RIH rats. Moreover, ciprofol upregulated α2GABAAR and downregulated NR2B and P-CaMKIIα in the rat spinal cord and hippocampus. CONCLUSIONS: Ciprofol alleviates RIH effectively, and the anti-hyperalgesic mechanisms may involve increasing α2GABAAR levels and decreasing NR2B and P-CaMKIIα levels in the spinal cord and hippocampus.

Versatile dodecyl trimethyl ammonium bromide modified γ-FeOOH for simultaneous removal and determination of As(⠤).

Inorganic arsenic pollution in water spreads all over the world, tremendously threatening environmental safety and human health. Herein, versatile dodecyl trimethyl ammonium bromide modified γ-FeOOH (DTAB-γ-FeOOH) was prepared for sportive removal and visual determination of As(Ⅴ) in water. DTAB-γ-FeOOH displays a nanosheet-like structure with a high specific surface area calculated as 166.88 m2 g-1. Additionally, DTAB-γ-FeOOH shows peroxidase-mimicking feature, which can catalyze colorless TMB to generate blue oxidized TMB (TMBox) in presence of H2O2. Removal experiments show that DTAB-γ-FeOOH exhibits good As(Ⅴ) removal efficiency because modification of DTAB makes γ-FeOOH carry abundant positive charges, improving affinity between DTAB-γ-FeOOH and As(Ⅴ). It is found that theoretical maximum adsorption capacity is up to 126.91 mg g-1. Moreover, DTAB-γ-FeOOH can resist interference of most of co-existing ions. After that, As(Ⅴ) was detected based on peroxidase-like DTAB-γ-FeOOH. As(Ⅴ) can be adsorbed onto DTAB-γ-FeOOH surface, markedly inhibiting its peroxidase-like activity. Based on it, As(Ⅴ) ranging from 1.67 to 3333.33 µg L-1 can be well detected, with a low LOD (0.84 µg L-1). The successful sorptive removal and visual determination of As(Ⅴ) from real environmental water indicated that DTAB-γ-FeOOH has great potential in the treatment of As(Ⅴ)-containing environment water.

Risk factors for pulmonary complications after laparoscopic liver resection: a multicenter retrospective analysis.

BACKGROUND: Postoperative pulmonary complications (PPCs) are among the most common complications after liver resection. Although the application of laparoscopy has reduced the incidence of PPCs, the rate of PPCs after laparoscopic liver resection (LLR) remains high and the risk factors for the same are unclear. Therefore, this study aimed to determine the risk factors for PPCs after LLR. METHODS: In this multicenter study, 296 patients underwent LLR from January 2019 to December 2020. Demographic data, pathological variables, and perioperative variables were reviewed. Univariate and multivariate analyses were performed to identify the independent risk factors for PPCs. RESULTS: Of the 296 patients, 80 (27.0%) developed PPCs. Patients with PPCs had significantly increased total costs, operation costs, length of stays, and postoperative hospital stays. Multivariate analysis identified three independent risk factors for PPCs after LLR: smoking [Odds ratio (OR): 5.413, 95% confidence intervals (CI): 2.446-11.978, P = < 0.001], location of lesion in segment 7 or 8 (OR 3.134, 95% CI 1.593-6.166, P = 0.001), duration of liver ischemia (OR 1.038, 95% CI 1.022-1.054, P < 0.001), and presence of intraoperative hypothermia (OR 3.134, 95% CI 1.593-6.166, P < 0.001). CONCLUSION: Smoking, location of lesion in segment 7 or 8, duration of liver ischemia and intraoperative hypothermia were independent risk factors for PPCs which significantly increased the length of stays and burden of healthcare costs.

Effect of Transcutaneous Electrical Acupoint Stimulation Combined with Transversus Abdominis Plane Block on Postoperative Recovery in Elderly Patients Undergoing Laparoscopic Gastric Cancer Surgery: A Randomized Controlled Trial.

INTRODUCTION: This study assessed the influence of transcutaneous electrical acupoint stimulation (TEAS) combined with transversus abdominis plane block (TAPB) on the recovery of elderly patients undergoing laparoscopic gastric cancer surgery. METHODS: Ninety patients (age ≥ 60 years) undergoing laparoscopic gastric cancer surgery were randomly divided into general anesthesia group (group G), TAPB group (group NG), and TEAS combined with TAPB group (group NTG). Patients in the NTG group received TEAS at PC6, LI4, and ST36 acupoints and TAPB. Patients in the NG group received TAPB. The quality of recovery (QoR) was assessed using the QoR-15 questionnaire. The percentages of T lymphocyte subsets were determined. Consumption of anesthetics, extubation time, visual analog scale (VAS) scores, time of first postoperative ambulation and flatus, and postoperative adverse events were also recorded. RESULTS: QoR-15 scores on postoperative day (POD) 3 and POD 7 were higher in the NTG group than in the G and NG groups (P < 0.05). On POD 1 and POD 3, the percentages of CD3+ and CD4+ T cells and the CD4+/CD8+ ratio were higher and the percentage of CD8+ T cells was lower in the NTG group than in the G and NG groups (P < 0.05). Remifentanil consumption, and the incidence of postoperative nausea and vomiting (PONV) were lower and extubation time and time of first postoperative flatus were shorter in the NTG group than in the G and NG groups (P < 0.05). Compared with the G group, the VAS scores on POD 1 were lower in the NG group and those on POD 2 were lower in the NTG group (P < 0.05). CONCLUSION: The combination of TEAS and TAPB ameliorated postoperative pain, improved immune and gastrointestinal function, reduced the incidence of PONV, and effectively promoted postoperative recovery in elderly patients undergoing laparoscopic gastric cancer surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100042119).

Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress.

Cancer pain is an important factor affecting life quality of patients especially in the advanced stage and relieving pain is one of fundamental strategies for cancer treatment. Opioids such as morphine are the most widely used in clinics. However, they have been reported to be associated with the occurrence and development of several types of cancer. Thus, search for an opioid that has analgesic effect and can retard cancer progress simultaneously is critical for cancer management. In this study, we first examined the expression of µ and κ (MOR and KOR) in cell lines and tumor tissues of hepatocellular carcinoma (HCC), a malignant tumor with high mortality, and then compared the effects of opioid receptors-specific agonists on malignant phenotypes of HCC cells in vitro and tumor growth in an HCC xenograft mouse model. KOR and MOR were found to be highly expressed in HCC cell lines and HCC tissues. The KOR-specific agonist U50488h, oxycodone (agonist for both KOR and MOR) and the MOR-specific agonist morphine inhibited HCC cell proliferation, while only U50488h and oxycodone suppressed colony formation and migration of HCC cells. U50488h and oxycodone, but not morphine, induced HCC apoptosis. Further detection of PERK, GRP78 and CHOP revealed that PERK signaling was upregulated by treatment with U50488h, while treatment with the PERK inhibitor GSK2656157 partially reversed the promotion of apoptosis and inhibition of cell proliferation by U50488h, indicating that endoplasmic reticulum stress is associated with its suppressing effect on HCC malignant phenotypes. Similar to the in vitro results, HCC growth was significantly reduced by administration of U50488h and oxycodone, but not by morphine, in the HCC xenograft mouse model. PERK and caspase-3 in the HCC tissues were up-regulated by U50488h treatment as detected by immunohistochemistry and western blotting. Taken together, our results revealed that activation of KOR by U50488h inhibited malignant phenotypes of HCC both in vitro and in vivo, while activation of MOR by morphine did not have such effect. Because of their dual roles in the relief of pain and in the suppression of malignant phenotypes, opioids such as U50488h that act on KOR should be considered as the first choice for HCC management.

Effects of PICCO in the guidance of goal-directed fluid therapy for gastrointestinal function after cytoreductive surgery for ovarian cancer.

OBJECTIVE: To explore the effects of PICCO on the Guidance of Goal-Directed Fluid Therapy for gastrointestinal function after cytoreductive surgery for ovarian cancer. METHODS: A total of 98 patients who received cytoreductive surgery for ovarian cancer under general anesthesia in our hospital were stochastically divided into the observation group and control group, with 49 cases in each group. The observation group received PICCO guided goal-directed fluid therapy, while patients in the control group were treated with conventional fluid therapy. At last, the total amount of infusion, the time required for postoperative gastrointestinal function recovery and related recovery rating, the first time to get out of bed after the surgery and the total hospitalization time were observed and compared between the two groups. RESULTS: The observation group had less time for gastrointestinal function recovery and had better functional recovery rating as well as other indicators than the control group. Besides, the observation group had less volume of infusion, needed shorter time to get out of bed and had a shorter length of hospital stay than the control group (all P<0.05). CONCLUSION: PICCO guided goal-directed liquid therapy can effectively improve the recovery of gastrointestinal function and reduce the length of stay in patients with ovarian cancer after cytoreductive surgery.

Computational Approaches in Preclinical Studies on Drug Discovery and Development.

Because undesirable pharmacokinetics and toxicity are significant reasons for the failure of drug development in the costly late stage, it has been widely recognized that drug ADMET properties should be considered as early as possible to reduce failure rates in the clinical phase of drug discovery. Concurrently, drug recalls have become increasingly common in recent years, prompting pharmaceutical companies to increase attention toward the safety evaluation of preclinical drugs. In vitro and in vivo drug evaluation techniques are currently more mature in preclinical applications, but these technologies are costly. In recent years, with the rapid development of computer science, in silico technology has been widely used to evaluate the relevant properties of drugs in the preclinical stage and has produced many software programs and in silico models, further promoting the study of ADMET in vitro. In this review, we first introduce the two ADMET prediction categories (molecular modeling and data modeling). Then, we perform a systematic classification and description of the databases and software commonly used for ADMET prediction. We focus on some widely studied ADMT properties as well as PBPK simulation, and we list some applications that are related to the prediction categories and web tools. Finally, we discuss challenges and limitations in the preclinical area and propose some suggestions and prospects for the future.

[Prognostic value of plasma microRNA-30b-5p combined with extravascular lung water index in patients with acute respiratory distress syndrome].

OBJECTIVE: To evaluate the prognostic value of plasma microRNA-30b-5p (miR-30b-5p) combined with extravascular lung water index (EVLWI) in patients with acute respiratory distress syndrome (ARDS). METHODS: 120 ARDS patients admitted to Danzhou People's Hospital from January 2016 to June 2019 were enrolled. The gender, age, body mass index (BMI), underlying diseases, etiology and baseline values of heart rate (HR), respiratory rate (RR), oxygenation index (OI), arterial partial pressure of carbon dioxide (PaCO2) and acute physiology and chronic health evaluation II (APACHE II) score were collected. According to the survival outcome during hospitalization, the patients were divided into survival group and death group. According to OI, the patients were divided into mild-moderate group (OI > 100 mmHg, 1 mmHg = 0.133 kPa) and severe group (OI ≤ 100 mmHg). The expression of plasma miR-30b-5p was detected by real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-PCR), and EVLWI was measured. The receiver operating characteristic (ROC) curve was drawn to analyze the value of plasma miR-30b-5p and EVLWI in predicting the death of patients with ARDS. Pearson correlation method was used to analyze the correlation between miR-30b-5p and EVLWI in ARDS patients with different prognosis during hospitalization. RESULTS: 120 patients with ARDS were enrolled in the analysis, with 42 patients in the death group, and 78 in the survival group; with 67 patients in the mild-moderate group, and 53 in the severe group. APACHE II score in the death group was higher than that in the survival group, but there was no significant difference in gender, age, BMI, underlying diseases, etiology or baseline values of HR, RR, OI, or PaCO2 between the two groups. The expression of plasma miR-30b-5p and EVLWI level in the death group were significantly higher than those in the survival group [miR-30b-5p (2-ΔΔCt): 2.28±0.74 vs. 0.52±0.06, EVLWI (mL/kg): 15.38±4.60 vs. 10.24±2.15,both P < 0.01]. The expression of plasma miR-30b-5p, EVLWI and mortality during hospitalization in the severe group were significantly higher than those in the mild-moderate group [miR-30b-5p (2-ΔΔCt): 2.05±0.65 vs. 0.93±0.17, EVLWI (mL/kg): 14.65±4.20 vs. 11.36±2.28, mortality during hospitalization: 58.5% (31/53) vs. 16.4% (11/67), all P < 0.01]. ROC curve analysis showed that the best cut-off value of plasma miR-30b-5p and EVLWI in predicting the death during hospitalization of ARDS patients were 1.62 and 13.28 mL/kg, respectively. Moreover, the area under ROC curve (AUC) of the combination of two parameters was significantly higher than that of the two alone (0.897 vs. 0.827, 0.785), with high sensitivity and specificity, 90.5% and 84.2%, respectively. Pearson correlation analysis showed that plasma miR-30b-5p in dead ARDS patients was significantly positively correlated with EVLWI (r = 0.768, P < 0.01), but the correlation was not found in surviving patients (r = 0.118, P > 0.05). CONCLUSIONS: The expression of plasma miR-30b-5p and EVLWI are related to the severity and prognosis of patients with ARDS, and the combination of the two has certain evaluation value for the prognosis of ARDS patients.